Cytotoxicity of the <scp>CD</scp>37 antibody <scp>BI</scp> 836826 against chronic lymphocytic leukaemia cells in combination with chemotherapeutic agents or <scp>PI</scp>3K inhibitors

Krause, Günter; Baki, I. Shukran; Kerwien, Susan; Knödgen, Eva; Neumann, Lars; Göckeritz, Elisa; Landwehr, Thomas; Heider, Karl-Heinz; Hallek, Michael

doi:10.1111/bjh.13635

Cited by 9 publications

(10 citation statements)

References 10 publications

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“…Beside effector mechanisms mediated by complement and immune cells, CD20 mAbs have been shown to induce direct apoptosis in lymphoma cell lines [49][50][51] and in CLL patients' leukaemia cells. 31,52 Consistently, our data show that RTX and OBZ induce cell death in CLL cells. Also, the BTK inhibitor ibrutinib and the PI3K-inhibitor idelalisib induce apoptosis in CLL, thus, confirming previous data.…”

Section: Figsupporting

confidence: 87%

“…Combinations of RTX or OBZ with ibrutinib or idelalisib induce approximately additive enhancement of cell death levels compared to those mediated by each single agent, which is consistent with data from Krause et al . on combination of RTX or OBZ with idelalisib 31 . This finding is of clinical relevance as these agents are currently used in combination in several clinical trials with promising results 42 …”

Section: Discussionmentioning

confidence: 82%

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Effects of CD20 antibodies and kinase inhibitors on B‐cell receptor signalling and survival of chronic lymphocytic leukaemia cells

et al. 2020

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Recently, clinical trial results have established inhibitors of B-cell receptor (BCR)-associated kinase (BAKi), with or without CD20 moniclonal antibodies (mAbs), as the preferred first-line treatment for most chronic lymphocytic leukaemia (CLL) patients. Using phosphospecific flow cytometry, we showed that in leukaemic cells from CLL patients the CD20 therapeutic antibodiesrituximab, ofatumumab, and obinutuzumabinhibited BCR signalling pathways targeting preferentially pBTK Y551but not BTK Y223and pAKT. On the contrary, ibrutinib and idelalisib reduced pBTK Y223 to a higher extent than pBTK Y551. The strong reduction of pAKT induced by idelalisib was enhanced by its combination with rituximab or ofatumumab. Moreover, CD20 mAbs and BAKi induced the death of leukaemia cells that was significantly potentiated by their combination. Analysis of the enhancement of cell death in these combinations revealed an approximately additive enhancement induced by rituximab or obinutuzumab combined with ibrutinib or idelalisib. Taken together, our data identified negative regulatory effects of CD20 mAbs and their combinations with BAKi on BCR signalling and cell survival in CLL. In conclusion, this study advances our understanding of mechanisms of action of CD20 mAbs as single agents or in combination with BAKi and could inform on the potential of combined therapies in ongoing and future clinical trials in patients with CLL.

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Section: Figsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 82%

Effects of CD20 antibodies and kinase inhibitors on B‐cell receptor signalling and survival of chronic lymphocytic leukaemia cells

et al. 2020

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“…Although phase 1/2 studies are limited by small patient numbers and dose variations, response rates with BI 836826 compare favorably to otlertuzumab or rituximab as single agents in CLL [9,10], and are in the range observed with ofatumumab and obinutuzumab [6,11]. Moreover, there is preclinical rationale to use BI 836826 in combination with cytotoxics and nonchemotherapy agents such as idelalisib [12,13].…”

Section: To the Editormentioning

confidence: 99%

Phase 1 first-in-human trial of the anti-CD37 antibody BI 836826 in relapsed/refractory chronic lymphocytic leukemia

et al. 2019

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“…13 Idelalisib was shown to enhance RTX- or BI 836826-induced cytotocity in CLL samples in vitro . 14 Moreover, the signalling pathway associated with CD37 ligation leads to several phosphorylations among PI3K delta recruitment, promoting cell survival. 15 Thus, combination treatment with a PI3K delta inhibitor and CD37 antibody has a biological rationale and is currently investigated as a first-line treatment for CLL patients in a clinical trial (NCT02538614).…”

mentioning

confidence: 99%

Idelalisib improves CD37 antibody BI 836826 cytotoxicity against chemo-resistant /relapse-initiating CLL cells: a rationale for combination treatment

Bétrian

Ysebaert

Heider

et al. 2016

Blood Cancer Journal

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Cytotoxicity of the CD37 antibody BI 836826 against chronic lymphocytic leukaemia cells in combination with chemotherapeutic agents or PI3K inhibitors

Cited by 9 publications

References 10 publications

Effects of CD20 antibodies and kinase inhibitors on B‐cell receptor signalling and survival of chronic lymphocytic leukaemia cells

Effects of CD20 antibodies and kinase inhibitors on B‐cell receptor signalling and survival of chronic lymphocytic leukaemia cells

Phase 1 first-in-human trial of the anti-CD37 antibody BI 836826 in relapsed/refractory chronic lymphocytic leukemia

Idelalisib improves CD37 antibody BI 836826 cytotoxicity against chemo-resistant /relapse-initiating CLL cells: a rationale for combination treatment

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